Annette Gilchrist PhD

Associate Professor


Midwestern University
Chicago College of Pharmacy
Department of Pharmaceutical Sciences
Alumni Hall Room 367
555 31st St.
Downers Grove, IL 60515

Office: (630) 515-7235
e-mail: agilchrist@midwestern.edu

 

EDUCATION

B.S. Biology Central State University 1987
M.S. Biochemistry University of Connecticut 1990
Ph.D. Immunology University of Connecticut - Health Center 1995

RESEARCH SUMMARY

G protein-coupled receptors (GPCRs) constitute the largest receptor family in the human genome and over the years they have proven themselves to be druggable targets. Binding of a ligand leads to subsequent activation of the GPCR with conformational changes that allow G protein coupling and ultimately cellular response driven through a variety of second messenger systems.  Most agonists and antagonists bind at the GPCR's orthosteric site, that is, the site recognized by the endogenous ligand. However, GPCRs possess additional "allosteric" sites that can be used to modulate receptor activity. In addition, most GPCRs can couple to more than one G protein, and different agonists can produce selective G protein activation.  Which G protein(s) gets activated by the GPCR determines the downstream cellular responses. My research focuses on allosteric and functionally selective modulators of GPCRs.

My primary receptors of interest are the chemokine receptors CCR1 and CCR5 as they relate to cancer, the recently deorphanized receptors FFAR2 and FFAR3 which may play a role in diabetes, and the thrombin receptor PAR1 and its role in cancer metastasis. In collaboration with Dr. Tiwari we have been looking at the role of G proteins in viral entry. Finally, we are developing novel tools to measure GPCR/G protein interactions and for this work utilize the parathyroid hormone receptor, PTH1R.

Research projects

Project I:

Investigate compounds to determine whether they are biased inhibitors of CCR1, or serve as dual antagonists targeting CCR1/CCR5. Compounds are evaluated using a variety of assays including competitive binding assays, calcium mobilization, b-arrestin translocation, proliferation, chemotaxis, bone resorption, and receptor internalization. We are interested in determining whether CCR1 and/or CCR5 antagonists will be an effective treatment for multiple myeloma. This work is done in collaboration with Dr. Bob Merritt at Kean University.

Project II:

Identify novel agonists for FFAR2 and FFAR3, two recently de-orphanized receptors that are activated by short chain fatty acids (acetate, propionate).  Their presence in pancreatic beta-cells suggests they may play a role in diabetes. Using rational drug design compounds have been identified from commercial libraries. These are screened using calcium mobilization, beta-arrestin translocation, proliferation, and chemotaxis assays. Potential hits are then used to evaluate SAR and synthesize novel compounds that are effective modulators of these GPCRs. This work is a collaborative effort with Dr. Brian Layden at the University of Illinois-Chicago.

Project III:

We are developing novel tools to assess receptor internalization (CCR1-Halotag fusion protein) and receptor-G protein coupling (protein-fragment complementation partners) using parathyroid hormone 1 receptor (PTH1R). The biased signaling of PTH1R is being done in collaboration with Dr. Paula Stern at Northwestern University.

Project IV:

PCR-based assays are being evaluated for their use in diagnosing Vancomycin Resistant Enterococcus (VRE) and Pseudomonas Aeruginosa (PA). To discriminate live from dead bacteria we are exploring the use of DNA cross-linking reagents such as ethidium monoazide. This project has moved into the validation phase working with clinical samples.

Selected Publications (see all publications)

Villa SR, Mishra RK, Zapater JL, Priyadarshini M, Gilchrist A, Mancebo H, Schiltz GE, Layden BT. Homology modeling of FFA2 identifies novel agonists that potentiate insuling secretion. J. Investig. Med. 2017 65:1116-1124. 

Villa SR, Priyadarshini M, Fuller MH, Bhardwaj T, Brodsky MR, Angueira AR, Mosser RE, Carboneau BA, Tersey SA, Mancebo H, Gilchrist A, Mirmira RG, Gannon M, Layden BT.  Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival. Sci. Reports. 2016 6:28159. 

Cohen A, Pattanaik S, Kumar P, Bies RR, de Boer A, Ferro A, Gilchrist A, Isbister GK, Ross S, Webb AJ. Organised crime against the academic peer review system. Br. J. Clin. Pharm. 2016 81:1012-1017.

Priyadarshini M, Wicksteed B, Schiltz GE, Gilchrist A, Layden BT. SCFA Receptors in Pancreatic beta Cells: Novel DIabetes Targets? Trends Endocrin. Metabol. 2016 27:653-664.

Mombers C, Legako K, Gilchrist A. Identifying medical wearables and sensor technologies that deliver data on clinical endpoints. Br. J. Clin. Pharm. 2016 81:196-198.

Curtis MJ, Bond RA, Spina D, Ahluwalia A, Alexander SP, Giembycz MA, Gilchrist A, Hoyer D, Insel PA, Izzo AA, Lawrence AJ, MacEwan DJ, Moon LD, Wonnacott S, Weston AH, McGrath JC. Experimental design and analysis and their reporting: new guidance for publication in BJP. Brit. J. Pharm. 2015 172:3461-3471.

Gilchrist A, Stern PH. Chemokines and Bone. Clin Rev Bone Miner Metab 2015 June 13:61-82.

Priyadarshini M, Villa SR, Fuller M, Wicksteed B, Mackay CR, Alquier T, Poitout V, Mancebo H, Mirmira RG, Gilchrist A, Layden BT. An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion. Mol. Endocrin. 2015 29:1055-1066.

Gilchrist A, Loke YK, Somogyi AA, Cohen AF, Ritter JM. BJCP 40th anniversary: moving forward, looking back. Br. J. Clin. Pharm. 2014 78:1175-1184.

Karash, A, Mazzoni, MR, Gilchrist, A. Pharmacological intervention at CCR1 and CCR5 as an approach for cancer: help or hindrance. Curr Top Med Chem 2014. Aug. 14(13): 1553-1573 PMID: 25159162

Gilchrist, A, Gauntner, TD,  Fazzini, A., Alley, KM, Pyen, DS, Ahn, J, Ha, SJ Willett, A, Sansom, SE, Yarfi, JL, Bachovchin, KA, Mazzoni, MR,  Merritt, JR. Identifying bias in CCR1 antagonists using radiolabeled binding, receptor internalization, b-arrestin translocation, and chemotaxis assays. Br. J. Pharm. 2014. Nov. 171(22):5127-38. PMID: 24990525

Asteriti, S, Daniele, S. Porchia, F, Dell'Anno, MT, Fazzini, A, Pugliesi, I, Trincavelli, ML,  Taliani, S, Martini, C, Mazzoni, MR,  Gilchrist , A.  Modulation of PAR1 signaling by benzimidazole compounds. Br. J. Pharm. 2012. Sep. 167:80-94. PMID: 22519452

Wang, J. Gilchrist, A, Stern, PH. Antagonist minigenes identify genes regulated by parathyroid hormone through G protein-selective and G protein co-regulated mechanisms in UMR-106 osteoblastic cells. Cell Signal. 2011 Feb. 23:380-388. PMID: 20940042 *Selected as a "must-read" article by Faculty 1000.

Eglen, RM, Gilchrist, A, Reisine, T. An overview of drug screening using primary and embryonic stem cells. Chem. High Throughput Screen. 2008 11:566-572. PMID: 18694393

Deng, X, Mercer, PF, Scotton, CJ, Gilchrist, A, Chambers, RC. Thrombin induces fibroblast CCL2/JE production and release via coupling of PAR1 to Gαq and cooperation between ERK1/2 and Rho kinase signalling pathways. 2008 Mol. Cell Biol. 19:2520-2533. PMID:18353977

Gilchrist, A, Blackmer, T. G-protein-coupled receptor pharmacology: Examining the edges between theory and proof. Curr. Opin. Drug Discov. Devel. 2007 10:446-451. PMID: 17659486

Aris, L, Gilchrist, A, Rens-Domiano, S, Meyer, C, Dratz, E, Hamm. HE. Structural Requirements for Gta_340-350 Stabilization of Metarhodopsin II. J. Biol. Chem. 2001 276:2333-2339. PMID: 11018024

Gilchrist, A, Bünemann, M, Li, A, Hosey, MM, Hamm, HE. A dominant negative strategy for studying roles of G proteins in vivo. J. Biol. Chem. 1999 274: 6610-6616. PMID: 10037756

Gilchrist, A, Mazzoni, MR, Dineen, BA, Dice, A, Linden, J, Proctor, WR, Lupica, CR, Dunwiddie, TV, Hamm, HE. Antagonists of the receptor-G protein interface block Gi-coupled signal transduction. J. Biol. Chem. 1998 273:14912-14919. PMID: 9614095

Zu, YL. Qi, J, Gilchrist, A, Fernandez, GA, Vazquez-Abad, D, Kreutzer, DL, Huang, CK, Sha'afi RI. p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation. J. Immol. 1998 160:1982-1989. PMID: 9469462